Silodosin is described in U.S. Pat. No. 5,387,603 as a selective α1-adrenoceptor antagonist and is currently marketed under brand name ‘RAPAFLO’ in US, ‘Silodyx’ in EP and ‘Rapilif’ in India. It is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia.
U.S. Pat. No. 5,387,603; discloses a multi-step process for the preparation of Silodosin which involves use of N-acylated indoline and N-Boc protected intermediates. Further the process involves complex steps like bromination and azidation, which are difficult to perform at large scale. Overall, the process is lengthy and requires steps like protection and deprotection, and some hideous steps making the process unsuitable for large scale production.
PCT application nos. 2012131710 and 2012147107; disclose the synthesis of Silodosin through formation of indoline derivatives like 3-(indolin-1-yl)propyl benzoate and 3-(7-cyano-5-(2-nitropropyl)indolin-1-yl)propyl benzoate. The method of preparation of these intermediates requires steps such as N-alkylation with propylbenzoate, C5-formylation, nitration, C7-formylation and cyanation. According to the disclosure, each step requires more time for the completion and also, there is a need of crystallisation of the products obtained before moving onto the next step. Synthesis of starting material like 3-(indolin-1-yl)propyl benzoate in itself is a time consuming two-step process and requires use of organic solvents. Major drawback of the above said process is that the overall process is very much time consuming and need extra efforts like crystallisation for the preparation of indoline intermediates making process un-amenable for large scale production.
Similarly, PCT application no. 201206229; discloses the synthesis of Silodosin through formation of benzyl-indoline derivatives like 1-(3-(benzyloxy)propyl)-5-formylindoline-7-carbonitrile and 1-(3-(benzyloxy)propyl)-5-(2-oxopropyl)indoline-7-carbonitrile. Synthesis of these intermediates is performed by using 1-(3-(benzyloxy)propyl)indoline-5-carbaldehyde as starting material which in turn is prepared by benzyl protection of 1-propanol followed by indoline N-alkyation and formylation.
The major drawback of above said process is three step synthesis of starting material 1-(3-(benzyloxy)propyl)indoline-5-carbaldehyde which is achieved in approx. 2.5-3 days. Secondly, product purification is done through column chromatography. The process is not only complicated but also require time engulfing and effortful steps which are not appropriate for plant scale production.
PCT application no. 2012014186; discloses preparation of indoline derivatives like phenyl 4-(7-cyano-5-(2-nitropropyl)indolin-1-yl)alkanoate by using phenyl 4-chloroalkanoate and indoline as starting materials through series of reactions. Silodosin is prepared from above said nitro derivative and the process is carried out through reductive hydrolysis, asymmetric amination, deprotection, condensation and ester reduction.
The process disclosed in above patent application is not only low yielding but also a lengthy process requiring extra steps of deprotection and ester reduction resulting into increase in the cost of production and hence unsuitable for commercial exploitation.
Japanese application no. 2002265444; discloses preparation of 1-(3-benzyloxypropyl)-5-(2-substituted propyl) indoline. The patent specifically discloses preparation of 5-(2-aminopropyl)-1-(3-benzyloxypropyl) indoline-7-carbonitrile from (R)-3-[1-(3-benzyloxypropyl)-7-cyanoindoline-5-yl]-2-methyl propionic acid by using pyrophoric reagents like n-BuLi, which is difficult to handle at large scale synthesis.
Taking into account the drawbacks of the aforementioned methods, the present invention provides some novel intermediates and their process of preparation, which can be effectively used for the synthesis of Silodosin and pharmaceutical acceptable salts thereof.